Non-abusable pharmaceutical composition comprising opioids

ABSTRACT

There is provided pharmaceutical compositions for the treatment of pain comprising a pharmacologically-effective amount of an opioid analgesic, or a pharmaceutically-acceptable salt thereof, presented in particulate form upon the surfaces of carrier particles comprising a pharmacologically-effective amount of an opioid antagonist, or a pharmaceutically-acceptable salt thereof, which carrier particles are larger in size than the particles of the opioid analgesic. The compositions are also useful in prevention of opioid abuse by addicts.

This application is the National Stage of international patentapplication Serial No. PCT/GB2007/004627, filed on Dec. 3, 2007, whichclaims priority under 35 U.S.C. §119(e) to U.S. provisional patentapplication Ser. No. 60/872,496, filed on Dec. 4, 2006.

This invention relates to new, fast acting, non-abusable pharmaceuticalcompositions that are useful in the treatment of pain, whichcompositions may be administered transmucosally and in particularsublingually.

Opioids are widely used in medicine as analgesics. Indeed, it ispresently accepted that, in the palliation of more severe pain, no moreeffective therapeutic agents exist.

The term “opioid” is typically used to describe a drug that activatesopioid receptors, which are found in the brain, the spinal cord and thegut. Three classes of opioids exist:

-   -   (a) naturally-occurring opium alkaloids. These include morphine        and codeine;    -   (b) compounds that are similar in their chemical structure to        the naturally-occurring opium alkaloids. These so-called        semi-synthetics are produced by chemical modification of the        latter and include the likes of diamorphine (heroin), oxycodone        and hydrocodone; and    -   (c) truly synthetic compounds such as fentanyl and methadone.        Such compounds may be completely different in terms of their        chemical structures to the naturally-occurring compounds.

Of the three major classes of opioid receptors (μ, κ and δ), opioids'analgesic and sedative properties mainly derives from agonism at the μreceptor.

Opioid analgesics are used to treat the severe, chronic pain of terminalcancer, often in combination with non-steroid anti-inflammatory drugs(NSAIDs), as well as acute pain (e.g. during recovery from surgery).Further, their use is increasing in the management of chronic,non-malignant pain.

Opioid-requiring cancer patients are usually given slow-release opiates(slow-release morphine or ketobemidone, or transdermal fentanyl). Acharacteristic feature of such treatments is periods of inadequateanalgesia (so-called “breakthrough” pain). Such periods are thought tobe due to increased physical activity of the patient. However, treatmentof breakthrough pain by administration of increased time-contingentdoses of long-acting analgesic formulations is known to cause, adverseside effects, including excess sedation, nausea, and constipation.

Presently-available oral, rectal and sublingual opioid analgesicformulations have relatively lengthy onset times and/or erraticabsorption characteristics, which makes then not entirely suitable forthe control of acute and/or breakthrough pain.

In order to obtain rapid onset of analgesia in the treatment of othertypes of acute pain, including operative pain, post-operative pain,traumatic pain, post-traumatic pain, and pain caused by severe diseases,such as myocardial infarction, nephrolithiasis, etc., opioid analgesicsare often administered parenterally (e.g. by intravenous orintramuscular injection). However, injections are an unpopular mode ofadministration, often being regarded as inconvenient and painful.

In view of the above, there is a real and growing clinical need forfast-acting orally-delivered drug compositions comprising opioidanalgesics. In particular, a need exists for further or betterfast-acting formulations comprising opioid analgesics, which may beadministered by a convenient route, for example transmucosally,particularly, as is usually the case, when such active ingredients areincapable of being delivered perorally due to poor and/or variablebioavailability.

However, a perennial problem with potent opioid analgesics such asfentanyl is one of abuse by drug addicts. Addicts normally abusepharmaceutical formulations by extracting a large quantity of activeingredient from that formulation into solution, which is then injectedintravenously. With most commercially-available pharmaceuticalformulations, this can be done relatively easily, which renders themunsafe or “abusable”. Thus, there also is a need for a fast acting,non-abusable pharmaceutical formulation comprising opioid analgesics.

Naloxone is a selective opioid antagonist that is used to reverse thepharmacological effects of opioids. Naloxone may therefore be used totreat narcotic drug overdose or to diagnose suspected opioid addiction.Naloxone has poor bioavailability when administered transmucosally buthas good bioavailability when administered by injection.

A simple mixture combination of the opioid partial agonist buprenorphineand naloxone for sublingual administration is available under thetrademark Suboxone®. This and other abuse-resistant opioid-containingformulations are reviewed by Fudula and Johnson in Drug and AlcoholDependence, 83S, S40 (2006). See also US patent applications US2003/0124061 and US 2003/0191147.

International patent applications WO 00/16750, WO 2004/067004 and WO2006/103418, all disclose drug delivery systems for the treatment ofe.g. acute pain by sublingual administration in which the activeingredient in microparticulate form and is adhered to the surface oflarger carrier particles in the presence of a bioadhesive and/ormucoadhesive promoting agent. Specific combinations of opioid analgesicsand opioid antagonists are not mentioned or suggested anywhere in thesedocuments.

In endeavouring to solve the above-mentioned problems, and to provide animproved, effective, fast-acting, non-abusable bioadhesive formulationcomprising a potent opioid analgesic, such as fentanyl, in combinationwith a sufficient dose of an opioid antagonist, such as naloxone, wehave found that it is not possible to provide both active ingredientsupon the surfaces of inert carrier particles as disclosed in theaforementioned patent documents. We have therefore devised an elegantsolution to this problem by providing particles of opioid analgesic drugupon the surfaces of carrier particles comprising an opioid antagonist,such as naloxone.

According to a first aspect of the invention there are providedparticulate pharmaceutical compositions for the treatment of paincomprising a pharmacologically-effective amount of an opioid analgesic,or a pharmaceutically-acceptable salt thereof, presented in particulateform upon the surfaces of carrier particles comprising apharmacologically-effective amount of an opioid antagonist, or apharmaceutically-acceptable salt thereof, which carrier particles arelarger in size than the particles of the opioid analgesic, whichcompositions are referred to hereinafter as “the compositions of theinvention”.

Compositions of the invention may further comprise a bioadhesion and/ora mucoadhesion promoting agent, which agent is, at least in part,presented on the surfaces of the carrier particles.

The compositions of the invention are interactive mixtures. The term“interactive” mixture will be understood by those skilled in the art todenote a mixture in which particles do not appear as single units, as inrandom mixtures, but rather where smaller particles (of, for example,opioid analgesic and/or bioadhesion and/or mucoadhesion promoting agent)are attached to (i.e. adhered to or associated with) the surfaces oflarger opioid antagonist-containing, or opioid antagonist-based, carrierparticles. Such mixtures are characterised by interactive forces (forexample van der Waals forces, electrostatic or Coulombic forces, and/orhydrogen bonding) between carrier and surface-associated particles (see,for example, Staniforth, Powder Technol., 45, 73 (1985)). In the finalmixture, the interactive forces need to be strong enough to keep theadherent particles at the carrier surface, in order to create ahomogeneous mixture.

The term “opioid analgesic” will be understood by the skilled person toinclude any substance, whether naturally-occurring or synthetic, withopioid or morphine-like properties and/or which binds to opioidreceptors, particularly the μ-opioid receptor, having at least partialagonist activity, thereby capable of producing an analgesic effect.

Opioid analgesics that may be mentioned include opium derivatives andthe opiates, including the naturally-occurring phenanthrenes in opium(such as morphine, codeine, thebaine and Diels-Alder adducts thereof)and semisynthetic derivatives of the opium compounds (such asdiamorphine, hydromorphone, oxymorphone, hydrocodone, oxycodone,etorphine, nicomorphine, hydrocodeine, dihydrocodeine, metopon,normorphine and N-(2-phenylethyl)normorphine). Other opioid analgesicsthat may be mentioned include fully synthetic compounds with opioid ormorphine-like properties, including morphinan derivatives (such asracemorphan, levorphanol, dextromethorphan, levallorphan, cyclorphan,butoiphanol and nalbufine); benzomorphan derivatives (such ascyclazocine, pentazocine and phenazocine); phenylpiperidines (such aspethidine (meperidine), fentanyl, alfentanil, sufentanil, remifentanil,ketobemidone, carfentanyl, anileridine, piminodine, ethoheptazine,alphaprodine, betaprodine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP), diphenoxylate and loperamide), phenylheptamines or “open chain”compounds (such as methadone, isomethadone, propoxyphene andlevomethadyl acetate hydrochloride (LAAM)); diphenylpropylaminederivatives (such as dextromoramide, piritramide, bezitramide anddextropropoxyphene); mixed agonists/antagonists (such as buprenorphine,nalorphine and oxilorphan) and other opioids (such as tilidine, tramadoland dezocine). More preferred opioid analgesics include buprenorphine,alfentanil, sufentanil, remifentanil and, particularly, fentanyl.

The term “opioid antagonist” will be understood by the skilled person toinclude any substance, whether naturally-occurring or synthetic, whichbinds to opioid receptors, particularly the μ-opioid receptor, having atleast partial antagonist activity, thereby for example at leastpartially reversing one or more of the pharmacological effects of anopioid analgesic mentioned hereinbefore. Opioid antagonists that may bementioned include naloxone, cyclazocine, nalmefene, opioid antagonistcompounds having the same pentacyclic nucleus as nalmefene, naltrexone,methylnaltrexone, nalorphine, nalbuphine, thebaine, levallorphon,pentazocine, oxymorphine, butorphanol, bupremorphine, levorphanol,meptazinol, dezocine, or pentazocine or their pharmacologicallyeffective salts or esters such as, but not limited to, theirhydrochlorides, maleates, tartrates and lactates. Preferred opioidantagonists include nalmefene, preferably methylnaltrexone, morepreferably naltrexone and, particularly, naloxone.

Any of the active ingredients mentioned in the above groupings may alsobe used in combination as required. Moreover, the above activeingredients may be used in free form or, if capable of forming salts, inthe form of a salt with a suitable acid or base. If the drugs have acarboxyl group, their esters may be employed. Active ingredients can beused as racemic mixtures or as single enantiomers.

The term “pharmacologically effective amount” refers to an amount of anactive ingredients, which is capable of conferring a desired therapeuticeffect on a treated patient, whether administered alone or incombination with another active ingredient. Such an effect may beobjective (i.e. measurable by some test or marker) or subjective (i.e.the subject gives an indication of, or feels, an effect).

Appropriate pharmacologically effective amounts of opioid analgesiccompounds include those that are capable of producing (preferably rapid)relief of pain when administered transmucosally, whereas appropriatepharmacologically effective amounts of opioid antagonist compounds inthe carrier particles must be sufficient so as not to compete with thepain-relieving effect of the opioid analgesic present in the compositionof the invention upon transmucosal administration, but to block theeffect of the opioid analgesic if an attempt is made by anopioid-addicted individual to inject a composition of the invention. Asstated above, we have found that this can be achieved elegantly bypresenting smaller microparticles of opioid analgesic on the surfaces oflarger carrier particles comprising opioid antagonist, and the skilledperson will appreciate that the relative sizes of the two activeingredients can be utilised to achieve the necessary relevant doses inthis respect.

The amounts of active ingredients that may be employed in compositionsof the invention may thus be determined by the physician, or the skilledperson, in relation to what will be most suitable for an individualpatient. This is likely to vary with the route of administration, thetype and severity of the condition that is to be treated, as well as theage, weight, sex, renal function, hepatic function and response of theparticular patient to be treated.

The total amount of opioid analgesic active ingredient that may beemployed in a composition of the invention will depend upon the natureof the relevant active ingredient that is employed, but may be in therange of about 0.0005%, such as about 0.1% (e.g. about 1%, such as about2%) to about 20%, such as about 10%, for example about 7%, by weightbased upon the total weight of the composition. The amount of thisactive ingredient may also be expressed as the amount in a unit dosageform (e.g. a tablet). In such a case, the amount of opioid analgesicactive ingredient that may be present may be sufficient to provide adose per unit dosage form that is in the range of between about 1 μg(e.g. about 5 μg) and about 20 mg (e.g. about 15 mg, such as about 10mg).

The total amount of opioid antagonist that may be employed in acomposition of the invention may be in the range about 1%, such as about2% (e.g. about 5%, such as about 10%) to about 98%, such as about 99%,for example about 99.9% (e.g. 99.9995%). The amount of this activeingredient may also be expressed as the amount in a unit dosage form(e.g. a tablet). In such a case, the amount of opioid antagonist activeingredient that may be present may be sufficient to provide a dose perunit dosage form that is in the range of between about 0.1 mg and about10 mg, such as about 1 to about 5 mg (e.g. about 4 mg).

The above-mentioned dosages are exemplary of the average case; therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

Opioid analgesic active ingredients in the compositions of the inventionare preferably in the form of microparticles, preferably with a weightbased mean diameter of between about 0.5 μm and about 15 μm, such asabout 1 μm and about 10 μm. The term “weight based mean diameter” willbe understood by the skilled person to include that the average particlesize is characterised and defined from a particle size distribution byweight, i.e. a distribution where the existing fraction (relativeamount) in each size class is defined as the weight fraction, asobtained e.g. by sieving.

Microparticles of active ingredients may be prepared by standardmicronisation techniques, such as grinding, dry milling, wet milling,precipitation, etc.

Preferably, opioid antagonist-containing carrier particles for use incompositions of the invention are of a size that is between about 50 andabout 1000 μm (e.g. about 800 μm, such as about 750 μm), and preferablybetween about 100 and about 600 μm.

It is possible for certain active ingredients that the relative sizesand amounts of the particles of opioid analgesic active ingredient andthe opioid antagonist-containing carrier particles that are employed aresufficient to ensure that the carrier particles may be at least about90% covered by the opioid analgesic, for example at least about 100% andup to about 200% (e.g. between about 130% and about 180%) covered. Theskilled person will appreciate in this context that “100% coverage” ofthe carrier particles by the opioid analgesic means that the relativeparticle sizes and amounts of the relevant particles that are employedare sufficient to ensure that the entire surface area of each carrierparticle could be covered by particles of the opioid analgesicnotwithstanding that other ingredients (e.g. mucoadhesion promotingagent) may also be present in a composition. Obviously, if other suchingredients are employed, then the actual degree of coverage of carrierparticles by active ingredient may be less than the amounts specifiedabove. 200% coverage means that there is sufficient particles of opioidanalgesic to cover the surfaces of the carrier particles twice over,notwithstanding the presence of other ingredients.

It is surprising that compositions with greater than 90% theoreticalcoverage are effective. Based on current knowledge, the skilled personwould understand that, in order to ensure rapid dissolution, it would beimportant to ensure that the relative sizes/amounts of opioidanalgesic/carrier particles are sufficient to ensure that 70% or less ofthe surfaces of the latter could be covered by the former.

As mentioned hereinbefore, compositions of the invention may compriseone or more bioadhesion and/or mucoadhesion promoting agent at least inpart presented on, and/or adhered to, the surface of an opioidantagonist-containing carrier particle, and may thus facilitate thepartial or complete adhesion of active ingredients to a biologicalsurface, such as a mucosal membrane.

The terms “mucoadhesive” and “mucoadhesion” refer to adhesion oradherence of a substance to a mucous membrane within the body, whereinmucous is present on the surface of that membrane (e.g. the membrane issubstantially (e.g. >95%) covered by mucous). The terms “bioadhesive”and “bioadhesion” refer to adhesion or adherence of a substance to abiological surface in a more general sense. Biological surfaces as suchmay include mucous membranes wherein mucous is not present on thatsurface, and/or surfaces that are not substantially (e.g. <95%) coveredby mucous. The skilled person will appreciate that, for example, theexpressions “mucoadhesion” and “bioadhesion” may often be usedinterchangeably. In the context of the present invention, the relevantterms are intended to convey a material that is capable of adhering to abiological surface when placed in contact with that surface (in thepresence of mucous or otherwise) in order to enable compositions of theinvention to adhere to that surface. Such materials are hereinafterreferred to together as “bio/mucoadhesives” or “bio/mucoadhesionpromoting agents”, and such properties together as “bio/mucoadhesion” or“bio/mucoadhesive”.

A variety of polymers known in the art can be used as bio/mucoadhesionpromoting agents, for example polymeric substances, preferably with anaverage (weight average) molecular weight above 5,000. It is preferredthat such materials are capable of rapid swelling when placed in contactwith water and/or, more preferably, mucous, and/or are substantiallyinsoluble in water at room temperature and atmospheric pressure.

Bio/mucoadhesive properties may be routinely determined in a generalsense in vitro, for example as described by G. Sala et al in Proceed.Int. Symp. Contr. Release. Bioact. Mat., 16, 420, 1989. Examples ofsuitable bio/mucoadhesion promoting agents include cellulose derivativessuch as hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose(HEC), hydroxypropyl cellulose (HPC), methyl cellulose, ethylhydroxyethyl cellulose, carboxymethyl cellulose, modified cellulose gumand sodium carboxymethyl cellulose (NaCMC); starch derivatives such asmoderately cross-linked starch, modified starch and sodium starchglycolate; acrylic polymers such as carbomer and its derivatives(Polycarbophyl, Carbopol®, etc.); polyvinylpyrrolidone; polyethyleneoxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such asgelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum;poly co-(methylvinyl ether/maleic anhydride); and crosscarmellose (e.g.crosscarmellose sodium). Such polymers may be crosslinked. Combinationsof two or more bio/mucoadhesive polymers can also be used.

Suitable commercial sources for representative bio/mucoadhesive polymersinclude: Carbopol® acrylic copolymer (BF Goodrich Chemical Co,Cleveland, 08, USA); HPMC (Dow Chemical Co., Midland, Mich., USA); NEC(Natrosol; Hercules Inc., Wilmington, Del. USA); HPC (Klucel®; DowChemical Co., Midland, Mich., USA); NaCMC (Hercules Inc. Wilmington,Del. USA); PEO (Aldrich Chemicals, USA); sodium alginate (Edward MandellCo., Inc., Carmel, N.Y., USA); pectin (BF Goodrich Chemical Co.,Cleveland, Ohio, USA); crosslinked polyvinylpyrrolidone (Kollidon CL®,BASF, Germany, Polyplasdone XL®, Polyplasdone XL-10® and PolyplasdoneINF-10®, ISP Corp., US); Ac-Di-Sol® (modified cellulose gum with a highswellability; FMC Corp., USA); Actigum (Mero-Rousselot-Satia, Baupte,France); Satiaxana (Sanofi Biolndustries, Paris, France); Gantrez® (ISP,Milan, Italy); chitosan (Sigma, St Louis, Miss., USA); and sodium starchglycolate (Primojel®, DMV International BV, Netherlands, Vivastar®, J.Rettenmaier & Söhne GmbH & Co., Germany, Explotab®, Roquette America,US).

Preferred bio/mucoadhesion promoting agents that may be employed incompositions of the invention include internally crosslinked sodiumcarboxymethylcellulose, such as croscarmellose sodium NF (e.g.Ac-Di-Sol® (FMC Corp., USA)) and crosslinked polyvinylpyrollodine (e.g.Kollidon CL®, BASF, Germany).

Depending on the type of the bio/mucoadhesion promoting agent used, therate and intensity of bio/mucoadhesion may be varied.

Suitably, the amount of bio/mucoadhesion promoting agent that is presentin a composition of the invention may be in the range of about 0.1 toabout 25% by weight based upon the total weight of the composition. Apreferred range is from about 0.5 to about 15% by weight, such as about1 to about 10% (e.g. about 2 to about 8%) by weight.

The carrier particles that are employed in compositions of the inventioncomprise opioid antagonist as defined herein. Carrier particles may ormay not consist essentially of opioid antagonist. By “consistingessentially” of opioid antagonist, we mean that the carrier particlescomprise at least about 95%, such as at least about 98%, more preferablygreater than about 99%, and particularly at least about 99.5% by weight(based on the total weight of the carrier particle) of such anantagonist. These percentages exclude the presence of trace amounts ofwater and/or any impurities that may be present in such materials, whichimpurities may arise following the production of such materials, eitherby a commercial or non-commercial third party supplier, or by a skilledperson making a composition of the invention. In any event, thepossibility of particles of opioid antagonist also being presented, atleast in part, upon the surfaces of, and/or between, such carrierparticles is not excluded.

When the carrier particles do not consist essentially of opioidantagonist, additional materials that may also form part of the carrierparticles include pharmaceutically-acceptable substances, such ascarbohydrates, e.g. sugar, mannitol and lactose;pharmaceutically-acceptable inorganic salts, such as sodium chloride,calcium phosphate, dicalcium phosphate hydrate, dicalcium phosphatedehydrate, tricalcium phosphate, calcium carbonate, and barium sulfate;polymers, such as microcrystalline cellulose, cellulose and crosslinkedpolyvinylpyrrolidone; or mixtures thereof.

When carrier particles do not consist essentially of opioid antagonist,additional materials may be admixed together with opioid antagonist by avariety of techniques, such as dry mixing, extrusion and/orspheronisation, or a process of granulation, which may comprise wetand/or dry granulation.

Wet granulation techniques are well known to those skilled in the artand include any technique involving the massing of a mix of dry primarypowder particles using a granulating fluid, which fluid comprises avolatile, inert solvent, such as water, ethanol or isopropanol, eitheralone or in combination, and optionally in the presence of a binder orbinding agent. The technique may involve forcing a wet mass through asieve to produce pellets by spheronisation or wet granules which arethen dried. Dry granulation techniques are also well known to thoseskilled in the art and include any technique in which primary powderparticles are aggregated under high pressure, including slugging androller compaction, for example as described hereinafter.

Primary particles of ingredients (e.g. opioid antagonist and othercarrier particle materials) may be processed by techniques, such asgrinding, dry milling, wet milling, precipitation, etc, prior togranulation.

Granulates comprising opioid antagonist may be further processedfollowing their formation and prior to admixing with other ingredientsto produce a composition of the invention. For example, a dry granulatemay be ground or milled using a suitable milling technique to produceparticulate material of a smaller size, which may also be sieved toseparate the desired size fraction. Wet granulate may be screened tobreak up agglomerates of granules and remove fine material. In eithercase, the unused fine material may be reworked to avoid waste. Suitablegranulate particle sizes are in the range of about 0.05 mm to about 1.2mm (e.g. about 1 mm), such as about 0.1 mm to about 1.0 mm (e.g. about0.8 mm), for example about 0.2 to about 0.6 mm.

Compositions of the invention, once prepared, are preferably directlycompressed/compacted into unit dosage forms (e.g. tablets) foradministration to mammalian (e.g. human) patients, for example asdescribed hereinafter.

A disintegrating agent, or “disintegrant” may also be included in thecomposition the invention, particularly those that are in the form oftablets for e.g. sublingual administration. Such an agent may be definedas any material that is capable of accelerating to a measurable degreethe disintegration/dispersion of a composition of the invention, and inparticular carrier particles, as defined herein. This may be achieved,for example, by the material being capable of swelling and/or expandingwhen placed in contact with water and/or mucous (e.g. saliva), thuscausing tablet formulations/carrier particles to disintegrate when sowetted. Suitable disintegrants include cross-linkedpolyvinylpyrrolidone, carboxymethyl starch and natural starch andmixtures thereof.

If present, disintegrating agent is preferably employed in an amount ofbetween 0.5 and 10% by weight based upon the total weight of thecomposition. A preferred range is from 1 to 8%, such as from about 2 toabout 7% (e.g. about 5%, such as about 4%) by weight.

It will be evident from the list of possible disintegrants providedabove that certain materials may function in compositions of theinvention in the form of tablets both as bio/mucoadhesion promotingagents and as disintegrating agents. Thus, these functions may both beprovided by different substances or may be provided by the samesubstance.

When the “same” material is employed as a bio/mucoadhesive and as adisintegrant, ant, the material can be said to be in two separatefractions (a bio/mucoadhesive fraction and a disintegrant fraction). Insuch instances, it is preferred that the particles within thedisintegrant fraction are coarser (i.e. are, relatively speaking, of alarger particle size) than those in the bioadhesive fraction (videinfra).

In any event, the skilled person will appreciate that, in compositionsof the invention in the form of tablets, any disintegrant (ordisintegrant fraction) will be largely not presented on (i.e. attachedto, adhered to and/or associated with) the surfaces of the carrierparticles, but rather will be largely presented (i.e. at least about60%, such as about 70%, e.g. about 80% and, more particularly, about 90%by weight presented) between such particles. Conversely,bio/mucoadhesive (or bio/mucoadhesive fraction) is always largelyassociated (i.e. is at least about 60%, such as about 70%, e.g. about80% and, more particularly, about 90% by weight associated) with thecarrier particles, that is to say presented on (i.e. attached to,adhered to and/or associated with) the surfaces of the carrierparticles, or presented within such particles (vide infra), or both.

Compositions of the invention in the form of tablets for e.g. sublingualadministration may also comprise a binder. A binder may be defined as amaterial that is capable of acting as a bond formation enhancer,facilitating the compression of the powder mass into coherent compacts.Suitable binders include cellulose gum and microcrystalline cellulose.If present, binder is preferably employed in an amount of between 0.5and 20% by weight based upon the total weight of the tablet formulation.A preferred range is from 1 to 15%, such as from about 2.0 to about 12%(e.g. about 10%) by weight.

Compositions of the invention may comprise a pharmaceutically acceptablesurfactant or wetting agent, which may enhance the hydration of activeingredients and carrier particles, resulting in faster initiation ofboth bio/mucoadhesion and dissolution. If present, the surfactant shouldbe provided in finely dispersed form and mixed intimately with theactive ingredients. Examples of suitable surfactants include sodiumlauryl sulphate, lecithin, polysorbates, bile acid salts and mixturesthereof. If present, the surfactant may comprise between about 0.1%(e.g. about 0.3%) and about 5% by weight based upon the total weight ofthe composition, and preferably between about 0.5 and about 3% byweight.

Suitable further additives and/or excipients that may be employed incompositions of the invention, in particular those in the form oftablets for e.g. sublingual administration may comprise:

-   -   (a) lubricants (such as sodium stearyl fumarate or, preferably,        magnesium stearate). When a lubricant is employed it should be        used in very small amounts (e.g. up to about 3%, and preferably        up to 2%, by weight based upon the total weight of the tablet        formulation);    -   (b) flavourings (e.g. lemon, menthol or, preferably, peppermint        powder), sweeteners (e.g. neohesperidin) and dyestuffs;    -   (c) antioxidants, which may be naturally occurring or otherwise        (e.g. vitamin C, vitamin E, β-carotene, uric acid, uniquion,        SOD, glutathione peroxidase or peroxidase catalase); and/or    -   (d) other ingredients, such as carrier agents, preservatives and        gliding agents.

Compositions of the invention may be prepared by standard techniques,and using standard equipment, known to the skilled person.

In one embodiment, particles of opioid analgesic may be dry mixed withopioid antagonist-containing carrier particles over a period of timethat is sufficiently long to enable appropriate amounts of activeingredients to adhere to the surface of the carrier particles (with orwithout the presence of bio/mucoadhesion promoting agent).

The skilled person will appreciate that, in order to obtain a dry powderformulation in the form of an interactive mixture, larger carrierparticles must be able to exert enough force to break up agglomerates ofsmaller particles. This ability will primarily be determined by particledensity, surface roughness, shape, flowability and, particularly,relative particle sizes.

Standard mixing equipment may be used in this regard. The mixing timeperiod is likely to vary according to the equipment used, and theskilled person will have no difficulty in determining by routineexperimentation a suitable mixing time for a given combination of opioidanalgesic active ingredient and carrier particle material(s).

Similarly, bio/mucoadhesion promoting agent (if present) may be admixedwith opioid antagonist-containing carrier particles may be mixedtogether with opioid antagonist-containing carrier particles for asufficient time in order to produce an ordered or interactive mixture.This results in discrete particles of bio/mucoadhesion promoting agentbeing presented on and/or adhered to the surfaces of the carrierparticles.

The bio/mucoadhesion promoting agent suitably has a particle size with aweight based mean diameter of between about 0.1 and about 100 μm (e.g.about 1 and about 50 μm).

Ordered, or interactive, mixtures may also be provided using techniquesother than dry mixing, which techniques will be well known to thoseskilled in the art.

Other ingredients (e.g. disintegrants and surfactants) may beincorporated by standard mixing as described above for the inclusion ofactive ingredients.

The compositions of the invention may be administered transmucosally,such as buccally, rectally, nasally or preferably sublingually by way ofappropriate dosing means known to the skilled person. A sublingualtablet may be placed under tongue, and the active ingredients absorbedthrough the surrounding mucous membranes.

In this respect, the compositions of the invention may be incorporatedinto various kinds of pharmaceutical preparations intended fortransmucosal (e.g. sublingual) administration using standard techniques(see, for example, Lachman et al, “The Theory and Practice of IndustrialPharmacy”, Lea & Febiger, 3^(rd) edition (1986) and “Remington: TheScience and Practice of Pharmacy”, Gennaro (ed.), Philadelphia Collegeof Pharmacy & Sciences, 19^(th) edition (1995)).

Pharmaceutical preparations for sublingual administration may beobtained by combining compositions of the invention with conventionalpharmaceutical additives and/or excipients used in the art for suchpreparations, and thereafter preferably directly compressed/compactedinto unit dosage forms (e.g. tablets). (See, for example, PharmaceuticalDosage Forms: Tablets. Volume 1, 2^(nd) Edition, Lieberman et al (eds.),Marcel Dekker, New York and Base1 (1989) p. 354-356 and the documentscited therein.) Suitable compacting equipment includes standardtabletting machines, such as the Kilian SP300 or the Korsch EKO.

Suitable final sublingual tablet weights are in the range of about 30 toabout 400 mg, such as about 40 (e.g. about 50) to about 200 mg, forexample about 50 (e.g. about 60) to 180 mg, more preferably betweenabout 60 (e.g. about 70) and about 160 mg. Suitable final tabletdiameters are in the range 4 to 10 mm, for example 5 to 9 mm, and morepreferably about 6 to about 8 mm.

Irrespective of the foregoing, compositions of the invention should beessentially free (e.g. less than about 20% by weight based on the totalweight of the formulation) of water. It will be evident to the skilledperson that “premature” hydration will dramatically decrease themucoadhesion promoting properties of a tablet formulation and may resultin premature dissolution of active ingredients.

Wherever the word “about” is employed herein in the context ofdimensions (e.g. tablet sizes and weights, particle sizes etc.), surfacecoverage (e.g. of opioid antagonist-containing carrier particles byparticles of opioid analgesic), amounts (e.g. relative amounts ofindividual constituents in a composition or a component of a compositionand absolute doses of active ingredients), it will be appreciated thatsuch variables are approximate and as such may vary by ±10%, for example±5% and preferably ±2% (e.g. ±1%) from the numbers specified herein.

Compositions of the invention may be administered by way of appropriatedosing means known to the skilled person. For example, a sublingualtablet may be placed under the tongue, and the active ingredientsabsorbed through the surrounding mucous membrane.

The compositions of the invention are useful in the treatment of painfor example the symptomatic treatment of pain, particularly severe;acute and/or breakthrough pain. According to a further aspect of theinvention there is provided a method of treatment of pain which methodcomprises administration of a composition of the invention to a personsuffering from, or susceptible to, such a condition.

For the avoidance of doubt, by “treatment” we include the therapeutictreatment, as well as the symptomatic treatment, the prophylaxis, or thediagnosis, of the condition.

The compositions of the invention enable the production of unit dosageforms that are easy and inexpensive to manufacture, and which enable therapid release and/or a rapid uptake of the active ingredients employedthrough the mucosa, such as the oral mucosa, thus enabling rapid reliefof pain symptoms, such as those described hereinbefore.

The compositions of the invention also have the advantage that, ifinjected by an opioid addict, they do not produce the euphoric effectsthat such an addict seeks and indeed induce opioid withdrawal syndrome.

The compositions of the invention may also have the advantage that theysubstantially reduce the degree of absorption of active ingredients viaswallowed saliva, as well as enabling the administration of “reduced”amounts of the opioid analgesic active ingredient that is employed, sosubstantially reducing the risk of side effects, as well as intra- andinterpatient variability of therapeutic response.

Compositions of the invention may also have the advantage that they maybe prepared using established pharmaceutical processing methods andemploy materials that are approved for use in foods or pharmaceuticalsor of like regulatory status.

Compositions of the invention may also have the advantage that they maybe more efficacious than, be less toxic than, be longer acting than, bemore potent than, produce fewer side effects than, be more easilyabsorbed than, and/or have a better pharmacokinetic profile than, and/orhave other useful pharmacological, physical, or chemical propertiesover, pharmaceutical compositions known in the prior art, whether foruse in the treatment of pain or otherwise.

The invention is illustrated by way of the following examples.

EXAMPLE 1 Naloxone/Fentanyl—Sublingual Tablets

An ordered mixture of micronised fentanyl citrate and a mucoadhesivecomponent adhered to the surface of water-soluble carrier particles,consisting of a dry granulate of a water-soluble excipient and naloxonehydrochloride is prepared as follows.

Active ingredients are accurately weighed out, along with the otherexcipients (see below), in appropriate proportions that enable theproduction of tablets with the absolute amounts of various ingredientsmentioned below.

Naloxone hydrochloride (Mallinckrodt, USA) and mannitol (Roquette,France) are mixed in a tumbling mixer (2 L Turbula W. A. Bachofen A G,Basel, Switzerland) for 60 minutes at 32 rpm.

The resultant mixture is then processed in a roller compaction intocompacts which are reduced in size by a rotor sieving mill. The particlesize of the resultant particles, which are used as carrier particles inthe formulation, is larger than 90 μm.

The carrier particles are then mixed with fentanyl citrate (Diosynth,Netherlands) in a tumbling mixer for 72 hours (laboratory scale) at 32rpm.

Croscarmellose sodium (Ac-Di-Sol®; FMC, USA) and silicifiedmicrocrystalline cellulose (ProSolv; Penwest pharmaceuticals Co, USA)are added to the resultant mixture and the mixing is continued foranother 30 minutes.

Finally, magnesium stearate (Peter Greven, Netherlands) is added to themixture and the mixing is continued for another 2 minutes.

The powder mixture is then compacted in a single punch press with 6 mmflat bevel edged punches, to give a tablet weight of 70 mg.

In-process controls, such as tablet weight, crushing strength anddisintegration time, are employed, with test samples being withdrawnthroughout the tabletting process. Tablets are packaged and labelled.

One tablet contains - Amount Ingredient (mg) Fentanyl citrate 0.314(corresponding to fentanyl base 200 μg) Naloxone hydrochloride 9.77(corresponding to naloxone base 8 mg) Mannitol 49.49 Silicifiedmicrocrystalline cellulose 9.35 croscarmellose sodium 0.73 magnesiumstearate 0.35 Total tablet weight 70.00

EXAMPLE 2 Naloxone/Fentanyl—Sublingual Tablets (Incorporating a DryGranulation Process Step)

Sublingual tablets were made using the same materials, in the sameproportions, as those specified in Example 1 above.

Carrier particles were manufactured by mixing mannitol and naloxone HClin the tumbling mixer at 32 rpm for 60 minutes. Dry granulation wasperformed by compaction of the mixture in a single punch press (KorschEKO, Germany) using 20 mm flat-faced punches. The compacts were thencrushed by sieving (1.4, 1.0 and 0.8 mm) and a final fraction of 90-800μm particles was obtained by sieving.

Fentanyl citrate was added to the carrier material in amountscorresponding to a batch size of 300 tablets. Mixing was carried outunder the same conditions as those described in Example 1.Croscarmellose sodium and silicified microcrystalline cellulose, andthen magnesium stearate, were added and admixed under the sameconditions as those described in Example 1.

The mixture was compressed into tablets in the single punch press using6 mm flat faced bevel edged punches.

EXAMPLE 3 Naloxone/Fentanyl—Sublingual Tablets (Incorporating a WetGranulation Process Step)

Sublingual tablets were made using the same materials, in the sameproportions, as those specified in Example 1 above.

To make carrier particles, mannitol and naloxone HCl were firstly mixedas described in Example 2 above. 18.5 mL of ethanol was then added tothe mixture, the wet mass was sieved (1.0 mm) and the granulate wasdried at room temperature for 18 hours. The granulate was then sieved toobtain particles with a fraction of 90-800 μm particles.

Fentanyl citrate, croscarmellose sodium and silicified microcrystallinecellulose, and then magnesium stearate, were all added and admixed underthe same conditions as those described in Examples 1 and 2 above. Themixture was compressed as described in Example 2.

What is claimed is:
 1. A particulate transmucosal pharmaceuticalcomposition in the form of a tablet suitable for sublingualadministration comprising a pharmacologically-effective amount of anopioid analgesic, or a pharmaceutically-acceptable salt thereof,presented in particulate form upon the surfaces of carrier particlescomprising a pharmacologically-effective amount of an opioid antagonist,or a pharmaceutically-acceptable salt thereof, which carrier particlesare larger in size than the particles of the opioid analgesic, whereinboth of said opioid analgesic and said opioid antagonist are deliveredtransmucosally, wherein the dose of opioid analgesic active ingredientper unit dosage form is in the range of between about 1 μg and about 20mg, and the dose of opioid antagonist active ingredient per unit dosageform is in the range of between about 0.1 mg and about 4 mg, and whereinthe opioid analgesic is selected from the group consisting of fentanyl,alfentanil, sufentanil, remifentanil and buprenorphine, and the opioidantagonist is selected from the group consisting of nalmefene,methylnaltrexone, naltrexone and naloxone.
 2. The particulatetransmucosal pharmaceutical composition of claim 1, wherein the opioidanalgesic is in the form of microparticles.
 3. The particulatetransmucosal pharmaceutical composition of claim 1, wherein the carrierparticles are of a size that is between about 50 and about 1,000 μm. 4.The particulate transmucosal pharmaceutical composition of claim 1,which further comprises a bioadhesion or a mucoadhesion promoting agent,which agent is, at least in part, presented on the surfaces of thecarrier particles.
 5. The particulate transmucosal pharmaceuticalcomposition of claim 4, wherein the amount of bioadhesion ormucoadhesion promoting agent present is in the range of about 0.1 toabout 25% by weight based upon the total weight of the composition. 6.The particulate transmucosal pharmaceutical composition of claim 4,wherein the bioadhesion or mucoadhesion promoting agent has a particlesize in the range of about 1 to about 100 μm.
 7. The particulatetransmucosal pharmaceutical composition of claim 1, wherein the carrierparticles further comprise a carbohydrate, a pharmaceutically-acceptableinorganic salt or a polymer.
 8. The particulate transmucosalpharmaceutical composition of claim 1, wherein the relative sizes andamounts of the particles of opioid analgesic and the carrier particlesthat are employed are sufficient to ensure that the carrier particlesare at least about 90% covered by the opioid analgesic particles.
 9. Theparticulate transmucosal pharmaceutical composition of claim 1, whereinthe composition further comprises a disintegrating agent.
 10. Theparticulate transmucosal pharmaceutical composition of claim 9, whereinthe disintegrating agent is selected from the group consisting ofcrosslinked polyvinylpyrrolidone, carboxymethyl starch, natural starchand mixtures thereof, wherein the amount of disintegrating agent isbetween about 2 and about 7% by weight based upon the total weight ofthe composition.
 11. A method which comprises administration of thecomposition of claim 1 to a patient.
 12. The method of claim 11, whereinsaid patient is suffering from or susceptible to pain.
 13. The method ofclaim 12, wherein said pain is selected from the group consisting ofsevere pain, acute pain and breakthrough pain.
 14. The method of claim11, wherein said composition is resistant to abuse by an opioid addict.15. The method of claim 11, wherein said patient is an opioid addict.16. A method of reversing one or more of the pharmacological effects ofan opioid analgesic, which method comprises providing for transmucosaladministration to a patient the composition of claim
 1. 17. The methodof claim 16 wherein the pharmacological effect is euphoria.
 18. A methodof reversing the euphoric effects that may be produced by injection of acomposition comprising an opioid analgesic, which method comprisesproviding for transmucosal administration to a patient the compositionof claim
 1. 19. A method of treating narcotic drug overdose ordiagnosing suspected opioid addiction, which method comprisesadministering the composition of claim 1 to a patient.